PubMed · 15170449
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Timothy J Yeatman. 2004. A renaissance for SRC.. https://doi.org/10.1038/nrc1366
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Drug response differs substantially in cancer patients due to inter- and intra-tumor heterogeneity. Particularly, transcriptome context, especially tumor microenvironment, has been shown playing a significant role in shaping the actual treatment outcome. In this study, we develop a deep variational autoencoder (VAE) model to compress thousands of genes into latent vectors in a low-dimensional space. We then demonstrate that these encoded vectors could accurately impute drug response, outperform standard signature-gene based approaches, and appropriately control the overfitting problem. We apply rigorous quality assessment and validation, including assessing the impact of cell line lineage, cross-validation, cross-panel evaluation, and application in independent clinical data sets, to warrant the accuracy of the imputed drug response in both cell lines and cancer samples. Specifically, the expression-regulated component (EReX) of the observed drug response achieves high correlation across panels. Using the well-trained models, we impute drug response of The Cancer Genome Atlas data and investigate the features and signatures associated with the imputed drug response, including cell line origins, somatic mutations and tumor mutation burdens, tumor microenvironment, and confounding factors. In summary, our deep learning method and the results are useful for the study of signatures and markers of drug response.
BACKGROUND: The specific inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, ZD1839 induces potent antitumoral effects on several advanced cancer types. The present study was undertaken to determine whether the combination of ZD1839 with an agent donating nitric oxide (NO(*)), sodium nitroprusside (SNP) results in a synergy of anticarcinogenic responses on metastatic prostate cancer (PC) cells. METHODS: The antiproliferative and apoptotic/necrotic effects of ZD1839 and SNP alone or in combination were estimated on EGF- and serum-stimulated LNCaP, DU145, and PC3 cells by MTT growth tests, trypan blue dye exclusion method, and flow cytometric analyses. Moreover, the cellular ceramide levels were evaluated by the diacylglycerol kinase enzymatic method and the amounts of cytosolic cytochrome c by ELISA assays. RESULTS: ZD1839 and SNP alone or in combination at lower concentrations induced an inhibition of EGF- and serum-stimulated growth of LNCaP, DU145, and PC3 concomitant with an arrest in the G1 phase of cellular cycle. Interestingly, the mixed ZD1839 and SNP also caused a more substantial apoptotic/necrotic death of these PC cells as compared to drugs alone. Moreover, we have observed that an inhibition of acidic sphingomyelinase, hydrogen peroxide (H(2)O(2)) accumulation and caspase cascades results in a significant reduction of apoptotic/necrotic death induced by mixed ZD1839 and SNP in EGF-stimulated PC3 cells. In addition, the combined ZD1839 plus SNP also induced a higher cellular ceramide and reactive oxygen species (ROS) production, mitochondrial transmembrane potential decrease, and cytochrome c amount released into cytosol as compared to drugs alone. CONCLUSIONS: The simultaneous use of EGFR inhibitor and compound releasing NO(*) might lead to a synergy in the ceramide and ROS production which might cause cellular membrane damages resulting in a massive apoptotic/necrotic death of metastatic PC cells.
Ppp5 (protein phosphatase 5) is a serine/threonine protein phosphatase that has been conserved throughout eukaryotic evolution. In mammalian cells, FLAG-tagged Ppp5 and endogenous Ppp5 are found to interact with endogenous Hsp (heat-shock protein) 70, as well as Hsp90. Incubation of cells with arachidonic acid or the microtubule-depolymerizing agent, nocodazole, causes loss of interaction of Hsp70 and Hsp90 with FLAG-tagged Ppp5 and increase of Ppp5 activity. In response to the same treatments, endogenous Ppp5 undergoes proteolytic cleavage of the N- and C-termini, with the subsequent appearance of high-molecular-mass species. The results indicate that Ppp5 is activated by proteolysis on dissociation from Hsps, and is destroyed via the proteasome after ubiquitination. Cleavage at the C-terminus removes a nuclear localization sequence, allowing these active cleaved forms of Ppp5 to translocate to the cytoplasm. The response of Ppp5 to arachidonic acid and nocodazole suggests that Ppp5 may be required for stress-related processes that can sometimes cause cell-cycle arrest, and leads to the first description for in vivo regulation of Ppp5 activity.